Aryl-substituted polycyclic amines, method for the production thereof, and use thereof as a medicament

ABSTRACT

The invention relates to aryl-substituted polycyclic amines of the formula I, especially bicyclic amines, and to the physiologically tolerated salts and physiologically functional derivatives thereof; 
                         
where the symbols and radicals are explained in the description as well as to pharmaceutical compositions and medical treatments employing these compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/675,646, filed Feb. 16, 2007, now allowed, which is a continuation ofInternational application No. PCT/EP2005/008,888, filed Aug. 16, 2005,which is incorporated herein by reference in its entirety; which claimsthe benefit of priority of German Patent Application No. 102004039789.9,filed Aug. 16, 2004.

FIELD OF THE INVENTION

The invention relates to aryl-substituted polycyclic amines, especiallybicyclic amines, and to the physiologically tolerated salts andphysiologically functional derivatives thereof.

BACKGROUND OF THE INVENTION

Compounds which have a similar overall structure to the aryl-substitutedpolycyclic amines described herein and have a pharmacological effecthave been described in the prior art. WO95/03302 discloses aryl ethersof bicyclic amino alcohols having a calcium-antagonistic effect.WO2002010146 describes an amidoaryl ether of hydroxyquinuclidine asantagonist of the 11CBY receptor for the treatment of obesity.

Compounds having an MCH-antagonistic effect for the treatment of obesityare described in the prior art (examples: WO2001021577, WO2003035624,WO2002089729, WO2002006245, WO2002002744, WO2002057233, WO2003045313,WO2003097047, WO2002010146, WO 2003087044).

The invention was based on the object of providing compounds which bringabout a weight reduction in mammals and are suitable for the preventionand treatment of obesity and diabetes and the diverse sequelae thereof.

Surprisingly, a series of compounds which modulate the activity of MCHreceptors has been found. The compounds are distinguished In particularby antagonism of the MCH1R.

SUMMARY OF THE INVENTION

The invention therefore relates to compounds of the formula I

-   -   in which the meanings are    -   A, B, D, G        -   independently of one another N, C(R3);    -   or        -   groups A and B or groups D and G are in each case C(R3) and            form together a 5- or 6-membered carbocyclic or heterocyclic            radical to result overall in a bicyclic system;    -   R3 H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,        O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,        (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,        O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R4)(R5), SO₂—CH₃, COOH,        COO—(C₁-C₆)-alkyl, CON(R6)(R7), N(R8)CO(R9), N(R10)SO₂(R11),        CO(R12), (CR13R14)_(x)—O(R15);    -   R4, R5, R6, R7, R8, R10        -   independently of one another H, (C₁-C₈)-alkyl;    -   or    -   R4 and R5, R6 and R7        -   form independently of one another optionally together with            the nitrogen atom to which they are bonded a 5-6 membered            ring which, apart from the nitrogen atom, may also include            0-1 further heteroatoms from the group of NH,            N—(C₁-C₆)-alkyl, oxygen and sulfur;    -   R9, R11, R12        -   independently of one another H, (C₁-C₈)-alkyl, aryl;    -   R13, R14        -   independently of one another H, (C₁-C₈)-alkyl;    -   R15 H, (C₁-C₆)-alkyl, aryl;    -   x 0, 1, 2, 3, 4, 5, 6;    -   R1 H, (C₁-C₈)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl; P1 X        N(R16), O, a bond, (R17)C═C(R18), C≡C, a group of the formula        (CR19R20)_(y), in which one or two (CR19R20) groups may be        replaced by Y to result in a chemically reasonable radical;    -   Y O, S, N(R21), C═O;    -   R16, R17, R18        -   independently of one another H, (C₁-C₈)-alkyl;    -   R19, R20        -   independently of one another H, (C₁-C₄)-alkyl, where R19 and            R20 in the y groups may in each case have identical or            different meanings;    -   y 1, 2, 3, 4, 5, 6;    -   R21 H, (C₁-C₈)-alkyl;    -   E 3-14 membered bivalent carbo- or heterocyclic ring structure        having 0-4 heteroatoms from the group of N, O and S, which may        optionally have substituents from the group of H, F, Cl, Br, I,        OH, CF₃, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,        O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,        (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,        (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl,        N(R22)(R23), SO₂—CH₃, CON(R24)(R25), N(R26)CO(R27),        N(R28)SO₂(R29), CO(R30) and be mono- or bicyclic, where E is not        a tetrazol-5-yl group;    -   R22, R23, R24, R25, R26, R28        -   independently of one another H, (C₁-C₈)-alkyl, aryl;    -   or    -   R22 and R23, R24 and R25        -   form independently of one another optionally together with            the nitrogen atom to which they are bonded a 5-6 membered            ring which, apart from the nitrogen atom, may also include            0-1 further heteroatoms from the group of NH,            N—(C₁-C₆)-alkyl, oxygen and sulfur;    -   R27, R29, R30        -   independently of one another H, (C₁-C₈)-alkyl, aryl;    -   K a bond, C≡C, (R31)C═C(R32), a group of the formula        (CR33R34)_(z) in which one or more (CR33R34) groups may be        replaced by Z to result in a chemically reasonable radical,        preferably a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R35), N(R36)CO,        CON(R37), (C(R38)(R39))_(v), CO, (R31)C═C(R32), C≡C, SCH₂,        SO₂CH₂;    -   v 1, 2, 3, 4;    -   R31, R32, R35, R36, R37, R38, R39        -   independently of one another H, (C₁-C₈)-alkyl;    -   Z O, S, N(R40), CO, SO, SO₂;    -   R33, R34        -   independently of one another H, (C₁-C₈)-alkyl,            hydroxy-(C₁-C₄)-alkyl, hydroxy,            (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, where R38 and R39 in the z            groups may in each case have identical or different            meanings;    -   z 1, 2, 3, 4, 5, 6;    -   R40 H, (C₁-C₈)-alkyl;    -   R2 H, (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy-(C₁-C₄)-alkyl,        (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi-,        tri- or spirocyclic ring which may include 0 to 4 heteroatoms        selected from the group of oxygen, nitrogen and sulfur, where        the ring system may additionally be substituted by one or more        of the following substituents: F, Cl, Br, CF₃, NO₂, CN,        (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        (C₀-C₈)-alkylene-aryl, oxo, CO(R41), CON(R42)(R43), hydroxy,        COO(R44), N(R45)CO(C₁-C₆)-alkyl, N(R46)(R47), SO₂CH₃, SCF₃ or        S—(C₁-C₆)-alkyl, where R2 is not a tetrazol-5-yl group;    -   R41, R42, R43, R44, R45, R46, R47        -   independently of one another H, (C₁-C₈)-alkyl;    -   or    -   R42 and R43, R46 and R47        -   independently of one another optionally together with the            nitrogen atom to which they are bonded a 5-6 membered ring            which, apart from the nitrogen atom, may also include 0-1            further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,            oxygen and sulfur;    -   E, K and R2        -   together form a tricyclic system where the rings may            independently of one another saturated, partially saturated            or unsaturated and in each case comprise 3-8 ring atoms;    -   L a group of the formula (CR48R49)_(m) in which one or more        (CR48R49) groups may be replaced by M to result in a chemically        reasonable radical, where L is O if Q is

-   -   where R91 is as defined below;    -   M O, S, N(R50), CO, SO, SO₂, preferably O, S, N(R50), CO, SO₂,        particularly preferably O, N(R50), very particularly preferably        O;    -   m 1, 2, 3, 4, 5, 6, preferably 1, 2, 3, 4, particularly        preferably 1, 2;    -   R48, R49, R50        -   independently of one another H, (C₁-C₆)-alkyl, aryl,            particularly preferably H, alkyl;

-   -   R91 H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, CO(R92), (CR93R94_(O′)-R95,        CO(CR93R94)_(p′)-R96;    -   R92 H, (C₁-C₈)-alkyl;    -   R93, R94        -   independently of one another H, (C₁-C₈)-alkyl, OH,            (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;    -   o′, p′ independently of one another 0, 1, 2, 3, 4, 5, 6;    -   R95, R96        -   independently of one another OH, O—(C₁-C₈)-alkyl,            CON(R97)(R98), N(R99)CO(R100), N(R101)(R102), CO₂(R103),            SO₂Me, CN, a 3-10 membered ring system having 0 to 3            heteroatoms selected from the group of N, O and S, which may            be substituted by one or more of the following substituents:            F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R104),            oxo, OH;    -   R97, R98, R99, R100, R103, R104        -   independently of one another H, (C₁-C₈)-alkyl;    -   or    -   R97 and R98        -   form optionally together with the nitrogen atom to which            they are bonded a 5-6 membered ring which, apart from the            nitrogen atom, may also include 0-1 further heteroatoms from            the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;    -   R101, R102        -   independently of one another H, (C₁-C₆)-alkyl,            (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl,            (C₂-C₆)-alkynyl, CO(R105), (CR106R107)_(q′)-R108,            CO(CR109R110)_(r′)-R111; or R101 and R102 form together with            the nitrogen atom to which they are bonded a 4 to            10-membered mono-, bi- or spirocyclic ring which, apart from            the nitrogen atom, comprises 0 to 3 additional heteroatoms            selected from the group of N, O and S and may additionally            be substituted by one or more of the following substituents:            F, Cl, Br, CF₃, O—(C₁-C₈)-alkyl, (C₁-C₆)-alkyl, CO(R112),            oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,            hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114), N(R115)CO(R116),            N(R117)(R118), CO₂(R119), SO₂Me;    -   R105, R106, R107, R108, R109, R110, R112, R113, R114, R115,        R116, R117, R118, R119        -   independently of one another H, (C₁-C₈)-alkyl;    -   or    -   R117 and R118        -   form optionally together with the nitrogen atom to which            they are bonded a 5-6 membered ring which, apart from the            nitrogen atom, may also include 0-1 further heteroatoms from            the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;    -   q′, r′ independently of one another 0, 1, 2, 3, 4, 5, 6;    -   R108, R11        -   independently of one another OH, O—(C₁-C₈)-alkyl,            CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO₂(R126),            SO₂Me, CN, a 3-10 membered ring system having 0 to 3            heteroatoms selected from the group of N, O and S, which may            be substituted by one or more of the following substituents:            F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R127),            oxo, OH;    -   R120, R121, R122, R123, R124, R125, R126, R127        -   independently of one another H, (C₁-C₈)-alkyl;    -   or    -   R120 and R121, R124 and R125        -   form independently of one another optionally together with            the nitrogen atom to which they are bonded a 5-6 membered            ring which, apart from the nitrogen atom, may also include            0-1 further heteroatoms from the group of NH,            N—(C₁-C₆)-alkyl, oxygen and sulfur;            the N-oxides thereof and the physiologically tolerated salts            thereof. The invention relates to compounds of the formula I            in the form of their racemates, enantiomer-enriched mixtures            and pure enantiomers and to their diastereomers and mixtures            thereof.

DETAILED DESCRIPTION

The compounds of the formula I are distinguished by improved metabolicstability with at the same time high activity compared with compounds ofsimilar structure.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3,R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32,R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46,R47, R48, R49, R50, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99,R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111,R112, R113, R114, R115, R116, R117, R118, R119, R120, R121, R122, R123,R124, R125, R126 and R127 may be either straight-chain, branched and/oroptionally substituted by substituents such as aryl, heteroaryl, alkoxyor halogen. This also applies if the alkyl, alkenyl and alkynyl radicalsare part of another group, e.g. part of an alkoxy group (such as(C₁-C₄)-alkoxy-(C₁-C₄-alkyl)). Suitable halogens are fluorine, chlorine,bromine and iodine, preferably fluorine, chlorine and bromine,particularly preferably fluorine.

Examples of alkyl groups are: methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl and octyl. Included therein are both the n isomers ofthese radicals and branched isomers such as isopropyl, isobutyl,isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl etc.Unless described otherwise, the term alkyl additionally includes alkylradicals which are unsubstituted or optionally substituted by one ormore further radicals, for example 1, 2, 3 or 4 identical or differentradicals such as aryl, heteroaryl, (C₁-C₄)-alkoxy or halogen. It ismoreover possible for the additional substituents to occur in anyposition of the alkyl radical. The alkyl radicals are preferablyunsubstituted, unless defined otherwise.

Cycloalkyl means for the purposes of the present application cycloalkyland cycloalkyl-alkyl (alkyl which is in turn substituted by cycloalkyl),with cycloalkyl having at least 3 carbon atoms. Examples of cycloalkylradicals are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Polycyclic ringsystems are also possible where appropriate, such as decalinyl,norbornanyl, bornanyl or adamantanyl. The cycloalkyl radicals may beunsubstituted or optionally substituted by one or more further radicalsas detailed by way of example above for the alkyl radicals. Thecycloalkyl radicals are preferably unsubstituted, unless definedotherwise.

Examples of alkenyl and alkynyl groups are: vinyl, 1-propenyl,2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl,ethynyl, 2-propynyl (propargyl), 2-butynyl or 3-butynyl.

Cycloalkenyl means for the purposes of the present applicationcycloalkenyl radicals and cycloalkenyl-alkyl radicals (alkyl which issubstituted by cycloalkenyl) which comprise at least three carbon atoms.Examples of cycloalkenyl are: cyclopentenyl, cyclohexenyl, cycloheptenyland cyclooctenyl.

The alkenyl radicals and cycloalkenyl radicals may have one to threeconjugated or unconjugated double bonds (that is also alk-dienyl andalk-trienyl radicals), preferably one double bond in a straight orbranched chain. The same applies to the triple bonds in alkynylradicals. The alkenyl and alkynyl radicals may be unsubstituted oroptionally substituted by one or more further radicals as detailed byway of example for the alkyl radicals above. The alkenyl and alkynylradicals are preferably unsubstituted, unless defined otherwise.

Aryl refers in the present invention to radicals derived from monocyclicor bicyclic aromatic systems comprising no ring heteroatoms. Where thesystems are not monocyclic, the term aryl includes for the second ringalso the saturated form (perhydro form) or the partially unsaturatedform (for example the dihydro form or tetrahydro form) where therespective forms are known and stable. The term aryl also includes inthe present invention for example bicyclic radicals in which both therings are aromatic and bicyclic radicals in which only one ring isaromatic. Examples of aryl are: phenyl, naphthyl, indanyl,1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or1,2,3,4-tetrahydronaphthyl. The aryl radicals are preferablyunsubstituted, unless defined otherwise. Aryl is particularly preferablyphenyl or naphthyl.

Heteroaryl radicals mean radicals derived from monocyclic or bicyclicaromatic systems which comprise ring heteroatoms, preferably N, O or S.Otherwise, that stated concerning aryl radicals applies to theheteroaryl radicals.

A “tricyclic system” means structures having 3 rings which are connectedtogether by more than one bond. Examples of such systems are fusedsystems having 3 rings and spirocyclic systems having a fused-on ringsystem.

The bivalent carbo- or heterocyclic ring structure E also includesstructures which are linked via one and the same atom to the twoadjacent groups K and X.

A polycyclic group means for the purposes of the present application agroup derived from spiranes, fused ring systems or bridged ring systems.Spiranes are distinguished by two rings having only one carbon atom incommon and the ring planes of the two rings being perpendicular to oneanother. In the fused ring systems, two rings are linked together sothat they have two atoms in common. This type of linkage involves an“ortho fusion”. Bridged ring systems are ring systems which have abridge of carbon atoms and/or heteroatoms between two nonadjacent atomsof a ring.

A “chemically reasonable radical” means for the purposes of the presentinvention a radical which is stable at room temperature and atmosphericpressure. For the purposes of the present invention, a “chemicallyreasonable radical” preferably means in the definitions of the groups L,X and K in the compounds of the formula (I) groups of the formula(CR48R49)_(m) (in the definition of L) (CR19R20)_(y) (in the definitionof X) or (CR33R34)_(z) (in the definition of K) which have noheteroatom-heteroatom linkages between the individual (CR48R49),(CR19R20) or (CR33R34) groups.

The compounds of the formula I may have one or more centers ofasymmetry. The compounds of the formula I may therefore exist in theform of their racemates, enantiomer-enriched mixtures, pure enantiomers,diastereomers and mixtures of diastereomers. The present inventionencompasses all these isomeric forms of the compounds of the formula I.These isomeric forms may be obtained by known methods, even if notexpressly described in some cases.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts) andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion, such as, for example,trifluoro acetate, likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Iof the invention, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention, as described, for example, in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

If radicals or substituents may occur more than once in the compounds ofthe formula I, they may all have the stated meanings independently ofone another and be identical or different.

L in the compounds of the formula I according to the inventionpreferably has the following meanings:

-   L a group of the formula (CR48R49)_(m) in which one or more    (CR48R49) groups may be replaced by M to result in a chemically    reasonable radical, where L is O if Q is

-   M O, S, N(R50), CO, SO, SO₂, preferably O, S, N(R50), CO, SO₂,    particularly preferably O, N(R50), very particularly preferably O;-   m 1, 2, 3, 4, 5, 6, preferably 1, 2, 3, 4, particularly preferably    1, 2;-   R48, R49, R50    -   independently of one another H, (C₁-C₆)-alkyl, aryl, preferably        H, (C₁-C₆)-alkyl, particularly preferably H.

The symbols in the compounds of the formula I preferably have thefollowing meanings:

-   A, B, D, G    -   independently of one another N, C(R3) or groups A and B or D and        G are each C(R3) and form together an ortho-phenylene unit to        result overall in a 1,4-disubstituted naphthalene system;        preferably independently of one another N or C(R3), where the        total number of nitrogen atoms in the ring is 0-2, preferably 0        or 1, particularly preferably A, B, D and G are C(R3);-   R3 H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R4)(R5), SO₂—CH₃,    CON(R6)(R7), N(R8)CO(R9), CO(R12), (CR13R14)_(x)—O(R15); preferably    H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃,    CON(R6)(R7), N(R8)CO(R9), CO(R12), (CR13R14)_(x)—O(R15),    particularly preferably H, F, C₁, CF₃, CN, (C₁-C₆)-alkyl,    (C(R13)(R14))_(x)—O(R15); very particularly preferably H, F,    (C₁-C₆)-alkyl; further preferably H, F, CH₃; especially preferably    H;-   R4, R5, R6, R7, R8    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R4 and R5, R6 and R7    -   independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur;-   R9, R12    -   independently of one another H, (C₁-C₈)-alkyl;-   R13, R14    -   H;-   R15 H, (C₁-C₆)-alkyl;-   x 0, 1, 2, preferably 0, 1, particularly preferably 1;-   R1 H, (C₁-C₈)-alkyl;-   X N(R16), a bond, (R17)C═C(R18), C≡C, CH₂—CH₂, YCH₂, CH₂Y,    preferably N(R16), a bond;-   Y O, S, N(R21);-   R16, R17, R18    -   independently of one another H, (C₁-C₈)-alkyl;-   R21 H, (C₁-C₈)-alkyl;-   E 3-8 membered bivalent carbo- or heterocyclic ring structure having    0-4 heteroatoms from the group of N, O and S, which may optionally    have substituents from the group of H, F, Cl, Br, OH, CF₃, CN, OCF₃,    O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,    O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R22)(R23), SO₂—CH₃,    N(R26)CO(R27), N(R28)SO₂(R29), CO(R30) and be mono- or bicyclic,    where E is not a tetrazol-5-yl group;    -   preferably 5-7 membered bivalent carbo- or heterocyclic ring        structure having 0-3 heteroatoms from the group of N, O and S,        which may optionally have substituents from the group of H, F,        Cl, Br, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—(C₀-C₈)-alkylene-aryl, S-aryl,        N(R22)(R23), SO₂—CH₃, N(R26)CO(R27), CO(R30) and be mono- or        bicyclic;    -   particularly preferably 5-7 membered bivalent carbo- or        heterocyclic ring structure having 0-2 heteroatoms from the        group of N, O and S, which may optionally have substituents from        the group of H, F, Cl, Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R22)(R23), SO₂—CH₃, CO(R30),        preferably H, F, Cl, Br, OH CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl;    -   e.g. E is selected from the group consisting of

-   -   which may optionally have substituents from the group of H, F,        Cl, Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, N(R22)(R23), SO₂—CH₃, CO(R30), preferably H, F,        Cl, Br, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl;        preferably

-   -   which may optionally have the aforementioned substituents;

-   R22, R23, R26, R28    -   independently of one another H, (C₁-C₈)-alkyl;

-   or

-   R22 and R23    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;

-   R27, R29, R30    -   independently of one another H, (C₁-C₈)-alkyl;

-   K a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R35), N(R36)CO, N—SO₂,    CON(R37), (C(R38)(R39))_(v), CO, (R31)C═C(R32), C≡C, SCH₂, SO₂CH₂,    preferably a bond, O, OCH₂, CH₂O, S, SO, SO₂, N(R35), N(R36)CO,    CON(R37), (C(R38)(R39))_(v), CO, (R31)C═C(R32), C≡C, SCH₂, SO₂CH₂,    particularly preferably OCH₂, CH₂O, N(R36)CO, CON(R37),    (C(R38)(R39))₂, (R31)C═C(R32), C≡C, SCH₂, SO₂CH₂, very particularly    preferably OCH₂, CH₂O, CON(R37), C≡C, SCH₂;

-   v 1, 2, 3, preferably 2;

-   R31, R32, R35, R36, R37, R38, R39    -   independently of one another H, (C₁-C₈)-alkyl;

-   R2 (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered    mono-, bi-, tri- or spirocyclic ring which may include 0 to 3    heteroatoms selected from the group of oxygen, nitrogen and sulfur,    where the ring system may additionally be substituted by one or more    of the following substituents: F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,    O—(C₁-C₈)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R41), CON(R42)(R43),    hydroxy, N(R45)CO(C₁-C₆)-alkyl, N(R46)(R47) or SO₂CH₃; preferably    (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered    mono- or bicyclic ring which may include 0 to 2 heteroatoms selected    from the group of oxygen, nitrogen and sulfur, where the ring system    may additionally be substituted by F, Cl, Br, CF₃, CN,    (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R41), CON(R42)(R43),    N(R45)CO(C₁-C₆)-alkyl or SO₂CH₃;

-   R41, R42, R43, R45, R46, R47    -   independently of one another H, (C₁-C₈)-alkyl;

-   or

-   R42 and R43, R46 and R47    -   form independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur;

-   L a group of the formula (C(R48)(R49))_(m) in which 0 or 1 member    may be replaced by an element from the group of O, N(R50),    preferably O, where L is O if Q is

-   m 1, 2, 3, 4, preferably 1 or 2;-   R48, R49    -   H;-   R50 H, (C₁-C₈)-alkyl, preferably H;-   Q

-   R91 H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, CO(R92), (CR93R94)_(O′)-R95, CO(CR93R94)_(p′)-R96;    preferably H, (C₁-C₆)-alkyl, (CR93R94)_(o′)-R95;-   R92 H, (C₁-C₈)-alkyl;-   R93, R94    -   independently of one another H, (C₁-C₈)-alkyl, OH,        (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, preferably H,        (C₁-C₈)-alkyl;-   o′, p′ independently of one another 0, 1, 2, 3, 4, 5, 6, preferably    0, 1, 2, 3;-   R95, R96    -   independently of one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98),        N(R99)CO(R100), N(R101)(R102), CO₂(R103), SO₂Me, CN, a 3-10        membered ring system having 0 to 3 heteroatoms selected from the        group of N, O and S, which may be substituted by one or more of        the following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH; preferably independently of        one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98), a 4-6 membered        ring system having 0 to 2 heteroatoms selected from the group of        N and O, which may be substituted by one or more of the        following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH, the ring system particularly        preferably being unsubstituted;-   R97, R98, R99, R100, R103, R104    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R97 and R98    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   R101, R102    -   independently of one another H, (C₁-C₆)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        CO(R105), (CR106R107)_(q′)-R108, CO(CR109R110)_(r′)-R111; or        R101 and R102 form together with the nitrogen atom to which they        are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring        which, apart from the nitrogen atom, comprises 0 to 3 additional        heteroatoms selected from the group of N, O and S and may        additionally be substituted by one or more of the following        substituents: F, Cl, Br, CF₃, O—(C₁-C₈)-alkyl, (C₁-C₆)-alkyl,        CO(R112), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114), N(R115)CO(R116),        N(R117)(R118), CO₂(R119), SO₂Me;-   R105, R106, R107, R108, R109, R110, R112, R113, R114, R115, R116,    R117, R18, R119    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R117 and R118    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   q′, r′ independently of one another 0, 1, 2, 3, 4, 5, 6;-   R108, R111    -   independently of one another OH, O—(C₁-C₈)-alkyl,        CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO₂(R126),        SO₂Me, CN, a 3-10 membered ring system having 0 to 3 heteroatoms        selected from the group of N, O and S, which may be substituted        by one or more of the following substituents: F, Cl, Br, CF₃,        (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R127), oxo, OH;-   R120, R121, R122, R123, R124, R125, R126, R127    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R120 and R121, R124 and R125    -   form independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur.

Particularly preferred compounds of the formula I are those in which

-   A, B, D, G are independently of one another N or C(R3), and the    total number of nitrogen atoms in this ring is 0-2, preferably 0 or    1, particularly preferably O.

In the compounds of the formula, the linkage between the group Q and thegroup

preferably takes place via a heteroatom, particularly preferably O or N,very particularly preferably O of the linker L.

The group Q in the compounds of the formula I particularly preferablyhas the following meanings:

preferably

-   R91 H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, CO(R92), (CR93R94)_(o′)-R95, CO(CR93R94)_(p′)-R96;    preferably H, (C₁-C₆)-alkyl, (CR93R94)_(o′)-R95;-   R92 H, (C₁-C₈)-alkyl;-   R93, R94    -   independently of one another H, (C₁-C₈)-alkyl, OH,        (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, preferably H,        (C₁-C₈)-alkyl;-   o′, p′ independently of one another 0, 1, 2, 3, 4, 5, 6, preferably    0, 1, 2, 3;-   R95, R96    -   independently of one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98),        N(R99)CO(R100), N(R101)(R102), CO₂(R103), SO₂Me, CN, a 3-10        membered ring system having 0 to 3 heteroatoms selected from the        group of N, O and S, which may be substituted by one or more of        the following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH; preferably independently of        one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98), a 4-6 membered        ring system having 0 to 2 heteroatoms selected from the group of        N and O, which may be substituted by one or more of the        following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH, the ring system particularly        preferably being unsubstituted;-   R97, R98, R99, R100, R103, R104    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R97 and R98    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   R101, R102    -   independently of one another H, (C₁-C₆)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        CO(R105), (CR106R107)_(q′)-R108, CO(CR109R110)_(r′)-R111; or        R101 and R102 form together with the nitrogen atom to which they        are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring        which, apart from the nitrogen atom, comprises 0 to 3 additional        heteroatoms selected from the group of N, O and S and may        additionally be substituted by one or more of the following        substituents: F, Cl, Br, CF₃, O—(C₁-C₈)-alkyl, (C₁-C₆)-alkyl,        CO(R112), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114), N(R115)CO(R116),        N(R117)(R118), CO₂(R119), SO₂Me;    -   R105, R106, R107, R108, R109, R110, R112, R113, R114, R115,        R116, R117, R118, R119    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R117 and R118    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   q′, r′ independently of one another 0, 1, 2, 3, 4, 5, 6;-   R108, R11    -   independently of one another OH, O—(C₁-C₈)-alkyl,        CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO₂(R126),        SO₂Me, CN, a 3-10 membered ring system having 0 to 3 heteroatoms        selected from the group of N, O and S, which may be substituted        by one or more of the following substituents: F, Cl, Br, CF₃,        (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R127), oxo, OH;-   R120, R121, R122, R123, R124, R125, R126, R127    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R120 and R121, R124 and R125    -   form independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur.

In the compounds of the formula I, Q is very particularly preferably

In a further very particularly preferred embodiment, Q has the followingmeaning:

where R91 has the abovementioned meanings and L is O.

In the compounds of the formula I L is preferably O or CH₂O,particularly preferably O, where L is O if Q is

Compounds of the formula I which are very particularly preferred arethose in which L-Q has the following meanings:

preferably

particularly preferably

very particularly preferably

-   R91 H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, CO(R92), (CR93R94)_(o′)-R95, CO(CR93R94)_(p′)-R96;    preferably H, (C₁-C₆)-alkyl, (CR93R94)_(o′)-R95;-   R92 H, (C₁-C₈)-alkyl;-   R93, R94    -   independently of one another H, (C₁-C₈)-alkyl, OH,        (C₃-C₈)-cycloalkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, preferably H,        (C₁-C₈)-alkyl;-   o′, p′ independently of one another 0, 1, 2, 3, 4, 5, 6, preferably    0, 1, 2, 3;-   R95, R96    -   independently of one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98),        N(R99)CO(R100), N(R101)(R102), CO₂(R103), SO₂Me, CN, a 3-10        membered ring system having 0 to 3 heteroatoms selected from the        group of N, O and S, which may be substituted by one or more of        the following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH; preferably independently of        one another OH, O—(C₁-C₈)-alkyl, CON(R97)(R98), a 4-6 membered        ring system having 0 to 2 heteroatoms selected from the group of        N and O, which may be substituted by one or more of the        following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,        O—(C₁-C₈)-alkyl, CO(R104), oxo, OH, the ring system particularly        preferably being unsubstituted;-   R97, R98, R99, R100, R103, R104    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R97 and R98    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   R101, R102    -   independently of one another H, (C₁-C₆)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        CO(R105), (CR106R107)_(q′)-R108, CO(CR109R110)_(r′)-R111; or        R101 and R102 form together with the nitrogen atom to which they        are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring        which, apart from the nitrogen atom, comprises 0 to 3 additional        heteroatoms selected from the group of N, O and S and may        additionally be substituted by one or more of the following        substituents: F, Cl, Br, CF₃, O—(C₁-C₈)-alkyl, (C₁-C₆)-alkyl,        CO(R112), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114), N(R115)CO(R116),        N(R117)(R118), CO₂(R119), SO₂Me;-   R105, R106, R107, R108, R109, R110, R112, R113, R114, R115, R116,    R117, R118, R119    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R117 and R118    -   form optionally together with the nitrogen atom to which they        are bonded a 5-6 membered ring which, apart from the nitrogen        atom, may also include 0-1 further heteroatoms from the group of        NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;-   q′, r′ independently of one another 0, 1, 2, 3, 4, 5, 6;-   R108, R111    -   independently of one another OH, O—(C₁-C₈)-alkyl,        CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO₂(R126),        SO₂Me, CN, a 3-10 membered ring system having 0 to 3 heteroatoms        selected from the group of N, O and S, which may be substituted        by one or more of the following substituents: F, Cl, Br, CF₃,        (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R127), oxo, OH;-   R120, R121, R122, R123, R124, R125, R126, R127    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R120 and R121, R124 and R125    -   form independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur.

In a particularly preferred embodiment of the present invention, thegroup L-Q in the compounds of the formula I is

In a further preferred embodiment, the group L-Q in the compounds of theformula I is

where R91 has the abovementioned meanings.

The present invention further relates to compounds of the formula I inwhich

-   A, B, D, G    -   are independently of one another N or C(R3), and the total        number of nitrogen atoms in this ring is 0-2, preferably 0 or 1,        particularly preferably 0;        where the other symbols in formula I have already been defined        above.

In a preferred embodiment, the present application relates to compoundsof the formula I

in which the meanings are

-   A, B, D, G    -   C(R3);-   R3 H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R4)(R5), SO₂—CH₃,    CON(R6)(R7), N(R8)CO(R9), CO(R12), (CR13R14)_(x)—O(R15); preferably    H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃,    CON(R6)(R7), N(R8)CO(R9), CO(R12), (CR13R14)_(x)—O(R15),    particularly preferably H, F, Cl, CF₃, CN, (C₁-C₆)-alkyl,    (C(R13)(R14))_(x)—O(R15); very particularly preferably H, F,    (C₁-C₆)-alkyl; further preferably H, F, CH₃; especially preferably    H;-   R4, R5, R6, R7, R8    -   independently of one another H, (C₁-C₈)-alkyl;-   or-   R4 and R5, R6 and R7    -   form independently of one another optionally together with the        nitrogen atom to which they are bonded a 5-6 membered ring        which, apart from the nitrogen atom, may also include 0-1        further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,        oxygen and sulfur;-   R9, R12    -   independently of one another H, (C₁-C₈)-alkyl;-   R13, R14    -   H;-   R15 H, (C₁-C₆)-alkyl;-   x 0, 1, 2, preferably 0, 1, particularly preferably 1.

In a further preferred embodiment, A, B, G and D in the compounds of theformula I are CH.

R2 is preferably selected from the group consisting of:

n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluorophenyl,p-chlorophenyl, p-bromophenyl, p-tolyl, p-methoxyphenyl,p-trifluoromethylphenyl,

K is preferably selected from the group consisting of:O, OCH₂, CH₂O, S, SO, SO₂, N(R35), N(R36)CO, CON(R37),(C(R38)(R39))_(v), CO, (R31)C═C(R32), C≡C, SCH₂, SO₂CH₂, preferablyOCH₂, CH₂O, N(R36)CO, CON(R37), (C(R38)(R39))₂, (R31)C═C(R32), C≡C,SCH₂, SO₂CH₂, particularly preferably OCH₂, CH₂O, CON(R37), C≡C, SCH₂;where

-   v 1, 2, 3, preferably 2;-   R31, R32, R35, R36, R37, R38, R39    -   are independently of one another H, (C₁-C₈)-alkyl.        X is preferably selected from the group consisting of bond and        N(R16), in which R16 is H or (C₁-C₈)-alkyl, particularly        preferably bond and NH.

The group E in the compounds of the formula I is defined above.According to the above definitions of E it is possible for E to be forexample a five- or six-membered ring. If the group E is a five-memberedring then the groups K and X in the compounds of the formula I are in apreferred embodiment disposed in positions 1 and 3 of the five-memberedring. If the group E is a six-membered ring then the groups K and X arein a preferred embodiment disposed in positions 1 and 4 (i.e. in paraposition relative to one another) of the six-membered ring.

E is particularly preferably selected from the group consisting of:

This invention further relates to the use of compounds of the formula Iand their pharmaceutical compositions as MCH receptor ligands. The MCHreceptor ligands of the invention are particularly suitable asmodulators of the activity of the MCH1R.

The role of MCH in regulating the energy balance has now been welldocumented (Qu, D. et al. Nature 1996, 380, 243-7; Shimada, M. et al.Nature 1998, 396, 670-4; Chen, Y et al. Endocrinology 2002, 143,2469-77; Endocrinology 2003, 144, 4831-40; Review: G. Hervieu, ExpertOpin. Ther. Targets 2003, 7, 495-511).

There are also indications that MCH antagonists can have a beneficialinfluence on centrally related disorders such as, for example,depressions (Borowsky, B. et al. Nature Medicine 2002, 8, 825-30;Review: G. Hervieu, Expert Opin. Ther. Targets 2003, 7, 495-511).

Compounds of this type are particularly suitable for the treatmentand/or prevention of

-   1. Obesity-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β cells    -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and the sequelae thereof such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations    -   low HDL cholesterol concentration-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   thromboses, hypercoagulable and prothrombotic stages (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Psychiatric indications such as    -   depressions    -   anxiety states    -   disturbances of the circadian rhythm    -   affection disorders    -   schizophrenia    -   addictive disorders        Formulations

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg)per day and per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.001 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Suitable infusion solutions for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampoules forinjections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, tablets or capsules, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I may be used as thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula I; as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one ormore surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anaqueous solution which is buffered where appropriate, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.A particular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I are distinguished by beneficial effectson lipid metabolism, and they are particularly suitable for weightreduction and for maintaining a reduced weight after weight reductionhas taken place in mammals and as anorectic agents. The compounds aredistinguished by their low toxicity and their few side effects. Thecompounds can be employed alone or in combination with otherweight-reducing or anorectic active ingredients. Further anorecticactive ingredients of this type are mentioned, for example, in the RoteListe, chapter 01 under weight-reducing agents/appetite suppressants,and may also include active ingredients which increase the energyturnover of the organism and thus lead to weight reduction or else thosewhich influence the general metabolism of the organism in such a waythat an increased calorie intake does not lead to an enlargement of thefat depots and a normal calorie intake leads to a reduction of the fatdepots of the organism. The compounds are suitable for the prophylaxisand, in particular, for the treatment of excessive weight or obesity.The compounds are further suitable for the prophylaxis and, inparticular, for the treatment of type II diabetes, of arteriosclerosisand for normalizing lipid metabolism and for the treatment of high bloodpressure.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, beneficial effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Examples which May be Mentioned are:

Antidiabetics

Suitable antidiabetics are disclosed for example in the Rote Liste 2001,chapter 12 or the USP Dictionary of USAN and International Drug Names,US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins andinsulin derivatives, such as, for example, Lantus® (see www.lantus.com)or Apidra®, and other fast-acting insulins (see, U.S. Pat. No.6,221,633), GLP-1 receptor modulators, as described in WO 01/04146 orelse such as those disclosed in WO 98/08871 of Novo Nordisk A/S forexample.

The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, potassiumchannel openers such as, for example, those disclosed in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism and lead to achange in the blood lipid composition, compounds which reduce foodintake or food absorption, PPAR and PXR modulators and activeingredients which act on the ATP-dependent potassium channel of the betacells.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with substances which influence hepaticglucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188).

In one embodiment, the compounds of the formula I are administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a biguanide such as, for example, metformin.

In a further embodiment, the compounds of the formula I are administeredin combination with a meglitinide such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione such as, for example, ciglitazone,pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 ofDr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are in combinationwith a DPPIV inhibitor as described, for example, in WO98/19998,WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO 02/38541,WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentaammonium chloride), P-31/98, LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered incombination with compounds with an inhibitory effect on SGLT-1 and/or 2,as disclosed directly or indirectly for example in PCT/EP03/06841,PCT/EP03/13454 and PCT/EP03/13455.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA-reductase inhibitor, such aslovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897, U.S. Pat.No. 6,277,831, EP 0683 773, EP 0683 774).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor asdescribed for example in WO 0250027, or ezetimibe, tiqueside,pamaqueside.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPARalpha agonist.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, e.g. CP-529, 414(torcetrapib).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP-citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist.

Antiobesity Agents

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor such as, forexample, orlistat.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In another embodiment, the further active ingredient is rimonabant.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amide;hydrochloride (CGP 71683A), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochlorides(SB-334867-A)), CB1 antagonists/inverse agonists, H3 antagonists/inverseagonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),BRS3 agonists, galanin antagonists, ghrelin antagonists, MCHantagonists, mGluR5 antagonists, opioid antagonists, growth hormone(e.g. human growth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), CNTF, CNTF derivatives (e.g.Axokine), TRH agonists (see, for example, EP 0 462 884), uncouplingprotein 2 or 3 modulators, leptin agonists (see, for example, Lee,Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso,Patricia. Leptin agonists as a potential approach to the treatment ofobesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists(bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569),PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the further active ingredient isleptin.

In one embodiment, the further active ingredient is dexamphetamine,amphetamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having effects on the coronary circulationand the vascular system, such as, for example, ACE inhibitors (e.g.ramipril), medicaments which act on the angiotensin-renine system,calcium antagonists, beta blockers etc.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered incombination with medicaments which are employed for cancer therapy andcancer prevention.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention.

The Activity of the Compounds was Tested as Follows:

Cloning of the cDNA for the human MCH receptor, preparation of arecombinant HEK293 cell line which expresses the human MCH receptor, andfunctional measurements with the recombinant cell line took place inanalogy to the description by Audinot et al. (J. Biol. Chem. 276,13554-13562, 2001). A difference from the reference was, however, theuse of the plasmid pEAK8 from EDGE Biosystems (USA) for the constructionof the expression vector. The host used for the transfection was atransformed HEK cell line named “PEAK Stable Cells” (likewise from EDGEBiosystems). Functional measurements of the cellular calcium flux afteraddition of agonist (MCH) in the presence of ligand of the inventiontook place with the aid of the FLIPR apparatus from Molecular Devices(USA), using protocols of the apparatus manufacturer.

Biological Test Model

The anorectic effect was tested on female NMRI mice. After withdrawal offeed for 17 hours, the test product was administered by gavage. Theanimals were housed singly with free access to drinking water and wereoffered condensed milk 30 minutes after administration of the product.The condensed milk consumption was determined every half hour for 7hours, and the general wellbeing of the animals was observed. Themeasured milk consumption was compared with the vehicle-treated controlanimals.

TABLE 1 Anorectic effect relating to compounds of the formula I,measured as the reduction in the cumulative milk consumption of treatedcompared with control animals. Oral dose Reduction in cumulative milkExample [mg/kg] consumption as % of the control 2 30 73 37 30 24

The examples and preparation methods detailed below serve to illustratethe invention without, however, restricting it.

Preparation Methods

The compounds of the invention of the formula I can be prepared with theaid of reactions known in principle. For example, the compounds wereobtained according to the following general reaction schemes.

Descriptions of the general methods used are to be found by way ofexample at the following places:

-   Methods A, B and C in Example 1;-   Method D in Example 2;-   Method E in Example 5;-   Method F in Example 78.

EXAMPLES General Explanations

a) Mode of Drawing the Structural Formulae

Only non-hydrogen atoms are depicted for clarity in the structuralformulae of the examples given.

b) Salt Forms

Many of the compounds of the invention are bases and can form salts withappropriately strong acids. In particular, after purification of thecompounds by HPLC chromatography using a trifluoroacetic acid-containingmobile phase they may be in the form of hydrotrifluoroacetates. Thesecan be converted into the free bases shown by simple treatment of asolution of the salts for example with sodium carbonate solution.

c) Units of the Characterizing Data

The unit of the stated molecular weights is “g/mol”. Peaks observed inthe mass spectrum are indicated as integral quotient of the molarmolecular ion mass and of the charge on the molecular ion (m/z).

Example 11-{4-[(1R,9aR)-1-(Octahydroquinolizin-1-yl)methoxy]phenyl}-3-(4-phenoxy-phenyl)urea

A solution of 4-phenoxyaniline (185 mg) in DMF (1 ml) was added dropwiseto a solution, cooled to 0° C., of carbonyldiimidazole (162 mg) in DMF(1 ml). After 30 minutes,4-[(1R,9aR)-1-(octahydroquinolizin-1-yl)-methoxy]-phenylamine (289 mg)in DMF (1 ml) was added dropwise. The reaction solution was kept firstlyat room temperature for 2 hours and then at 80° C. for 30 minutes. Themixture was added dropwise to water (20 ml), and the resultingprecipitate was filtered off with suction and washed with water.Alternatively, the product can also be extracted with ethyl acetate andpurified after concentration by chromatography. The product with themolecular weight of 471.60 (C29H33N3O3); MS (ESI): 472 (M+H+) wasobtained in this way.

4-[(1R,9aR)-1-(Octahydroquinolizin-1-yl)-methoxy]phenylamine

Method B

A suspension of (1R,9aR-1-(4-nitrophenoxymethyl)-octahydroquinolizine(800 mg) and palladium(II) hydroxide (20% on carbon; 0.15 g) in ethanol(30 ml) was vigorously stirred under a hydrogen atmosphere (atmosphericpressure) for 3 hours. The catalyst was then removed by filtration, andthe filtrate was concentrated. The product with the molecular weight of260.38 (C16H24N2O); MS (ESI): 261 (M+H+) was obtained in this way.

(1R,9aR)-1-(4-Nitrophenoxymethyl)octahydroquinolizine

Method C

(1R,9aR)-1-(Octahydroquinolizin-1-yl)methanol (2.5 g) was added to asuspension of sodium hydride (60% in oil, 710 mg) in DMF (20 ml) and,after gas evolution ceased, 4-fluoronitrobenzene (2.51 g) was added.After 2 hours, the reaction mixture was hydrolyzed with water and thenpartitioned between ethyl acetate and dilute hydrochloric acid. Theaqueous phase was made alkaline with sodium hydroxide solution andextracted twice with ethyl acetate. The two ethyl acetate phases werecombined, dried over magnesium sulfate and concentrated. The productwith the molecular weight of 290.37 (C16H22N2O3); MS (ESI): 291 (M+H+)was obtained in this way.

Example 24-Butoxy-N-{4-[(1R,9aR)-1-(octahydroquinolizin-1-yl)methoxy]phenyl}-benzamide

TOTU (78 mg) and ethyldiisopropylamine (31 mg), followed by4-[(1R,9aR)-1-(octahydroquinolizin-1-yl)methoxy]phenylamine (62 mg),were added to a solution of 4-butoxybenzoic acid (46.4 mg) in DMF (2 ml)at 0° C. After a reaction time of three hours at room temperature, themixture was diluted with sodium bicarbonate solution and ethyl acetate.After separation of the phases, the aqueous phase was extracted withethyl acetate, and the combined organic phases were dried over magnesiumsulfate and concentrated. The residue was purified by preparative HPLC.The product with the molecular weight of 436.60 (C27H36N2O3); MS (ESI):437 (M+H+) was obtained in this way.

Example 31-[4-((1S*,3R*,5R*)-8-Methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenyl]-3-(4-phenoxyphenyl)urea

4-Phenoxyaniline was reacted by method A with4-((1S*,3R*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenylamine.The product with the molecular weight of 443.55 (C27H29N3O3); MS (ESI):444 (M+H+) was obtained in this way.

4-((1S*,3R*,5R*)-8-Methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenylamine

(1S*,3R*,5R*)-8-Methyl-8-azabicyclo[3.2.1]octan-3-ol was reacted bymethod C and B with 4-fluoronitrobenzene and then hydrogenated. Theproduct with the molecular weight of 232.33 (C14H20N2O); MS (ESI): 233(M+H+) was obtained in this way.

Example 44-Butoxy-N-[4-((1S*,3R*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)-phenyl]benzamide

4-Butoxybenzoic acid was reacted by method D with4-((1S*,3R*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenylamine.The product with the molecular weight of 408.55 (C25H32N2O3); MS (ESI):409 (M+H+) was obtained in this way.

Example 5 4-(4-Chlorophenyl)piperidine-1-carboxylic acid[4-((1S*,3S*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenyl]amide

Method E

Di-tert-butyl azodicarboxylate (69.5 mg) was added to a stirredsuspension of triphenylphosphine (polymer, 80 mg) in dichloromethane (3ml) at 0° C. and, after 5 minutes, a mixture of tropine,4-(4-chlorophenyl)piperidine-1-carboxylic acid (4-hydroxyphenyl)amide(100 mg) and dichloromethane (3 ml) was added. After 12 hours at roomtemperature, the polymer was filtered off with suction and the filtratewas concentrated. The residue was purified by preparative HPLC. Theproduct with the molecular weight of 454.02 (C26H32ClN3O2); MS (ESI):454 (M+H+) was obtained in this way.

4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-hydroxyphenyl)amide

Carbonyldiimidazole (1.48 g) was added to a solution of 4-aminophenol(1.0 g) in DMF (10 ml) at 0° C. After 10 minutes, a mixture of4-(4-chlorophenyl)piperidine (hydrochloride; 2.13 g), Hünig's base (1.18g) and DMF (10 ml) was added. After two hours, the reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic phasewas washed with water, dried over magnesium sulfate, filtered andconcentrated. The product with the molecular weight of 330.82(C18H19ClN2O2); MS (ESI): 331 (M+H+) was obtained in this way.

Example 6 4-(4-Chlorophenyl)piperidine-1-carboxylic acid[4-((1S,3R*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenyl]amide

4-(4-Chlorophenyl)piperidine was reacted by method A with[4-((1S*,3R*,5R*)-8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)phenyl]amide.The product with the molecular weight of 454.02 (C26H32ClN3O2); MS(ESI): 454 (M+H+) was obtained in this way.

Example 7 4-(4-Chlorophenyl)piperidine-1-carboxylic acid[4-(4-oxooctahydroquinolizin-1-yloxy)phenyl]amide

4-(4-Chlorophenyl)piperidine was reacted by method E with(hexahydropyrrolizin-1-yl)methanol. The product with the molecularweight of 454.02 (C26H32ClN3O2); MS (ESI): 454 (M+H+) was obtained inthis way.

(Hexahydropyrrolizin-1-yl)methanol

Lithiumaluminumhydride (0.3 g) was added to a solution ofhexahydropyrrolizine-1-carboxylic acid ethyl ester (0.97 g) in THF (3ml). After 12 hours, the reaction mixture was diluted with diethyl etherand hydrolyzed by cautious addition of water (0.7 ml). The resultingprecipitate was filtered off and the filtrate was concentrated. Theproduct with the molecular weight of 141.21 (C8H15NO); MS (ESI): 142(M+H+) was obtained in this way.

Hexahydropyrrolizine-1-carboxylic acid ethyl ester

A mixture of rac-proline (1.15 g), ethyl acrylate (1.20 g), toluene (80ml) and paraformaldehyde (3.6 g) was heated to reflux for 3 hours. Themixture was concentrated and the residue was filtered through silicagel. The product with the molecular weight of 183.25 (C10H17NO2); MS(ESI): 184 (M+H+) was obtained in this way.

The compounds in Table 2a and Table 2b were obtained by method A (forureas) or method D (for amides).

TABLE 2a ESI- Ex. Molecular Molecular MS No. Structure formula weight[M + H]⁺ 8

C28H38N2O3 450.63 451 9

C30H34N2O2 454.62 455 10

C30H34N2O2 454.62 455 11

C29H32N2O3 456.59 457 12

C29H36N2O3 460.62 461 13

C30H31F3N2O2 508.59 509 14

C29H38N2O2 446.64 447 15

C29H31FN2O2 458.58 459 16

C29H31FN2O2 458.58 459 17

C28H34ClN3O2 480.06 480 18

C27H35BrN4O2 527.51 528 19

C24H27F3N2O3 448.49 449 20

C30H34N2O3 470.62 471 21

C29H30ClFN2O3 509.03 509 22

C29H37ClN2O2 481.08 481 23

C30H34N2O3 470.62 471 24

C30H35N3O3 485.63 486 25

C29H32FN3O3 489.60 490 26

C30H32F3N3O3 539.60 540 27

C28H37N3O3 463.63 464 28

C27H36N4O3 464.61 465 29

C26H31N5O4S2 541.70 542 30

C28H38N4O2 462.64 463 31

C30H41N5O3 519.69 520 32

C29H33N3O3 471.60 472 33

C30H35N3O2 469.63 470 34

C28H44N4O2 468.69 469 35

C27H35FN4O2 466.60 467 36

C27H36N2O3 436.60 437 37

C28H36ClN3O2 482.07 482 38

C29H32N2O2 440.59 441 39

C25H29ClN4O3 468.99 469 40

C27H28ClN3O4 493.99 494 41

C29H33N3O3 471.60 472 42

C26H35N3O3 437.59 438 43

C29H35N3O3 473.62 474 44

C26H29N3O3S 463.60 464 45

C29H37N3O3 475.64 476 46

C27H31N3O2S 461.63 462 47

C28H36N2O3 448.61 449 48

C28H36N2O3 448.61 449 49

C28H35FN2O3 466.60 467 50

C26H29ClN4O2 465.00 465 51

C27H30N2O4 446.55 447 52

C28H31N3O5 489.58 490 53

C29H30N2O3 454.57 455 54

C27H33ClN4O2 481.04 482 55

C28H36ClN3O3 498.07 498

TABLE 2b Ex. Molecular Molecular ESI-MS No. Structure formula weight[M + H]⁺ 56

C26H33ClN4O2 469.03 469 57

C25H30ClN3O2 439.99 440 58

C25H30N2O3 406.53 407 59

C24H24N2O4 404.47 405 60

C26H32N2O3 420.56 421 61

C27H34N2O3 434.58 435 62

C27H34ClN3O2 468.04 468 63

C26H32N2O3 420.56 421 64

C25H26N2O4 418.50 419 65

C26H32ClN3O2 454.02 454 66

C26H32N2O3 420.56 421 67

C25H29ClN4O2 452.99 453 68

C26H33N3O2 419.57 420 69

C25H32N2O3 408.55 409 70

C27H27FN2O2 430.53 431 71

C27H33N3O3 447.58 448 72

C25H30N2O3 406.53 407 73

C27H26N2O3 426.52 427 74

C25H24ClN3O5 481.94 482 75

C24H30N2O3 394.52 395 76

C27H28N2O3 428.54 429 77

C27H33ClN2O2 453.03 453

Example 78 4-(4-Chloro-phenyl)-piperidine-1-carboxylic acid{4-((1S*,3R*,5R*)-[8-(tetrahydrofuran-3-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yloxy]-phenyl}-amide

A mixture of 4-(4-Chloro-phenyl)-piperidine-1-carboxylic acid[4-((1S*,3R*,5R*)-8-aza-bicyclo[3.2.1]oct-3-yloxy)-phenyl]-amide (50mg), tetrahydrofuran-3-carbaldehyde (10 mg), acetic acid (7 mg), THF (2ml) was mixed with sodium cyanoborohydride (polymer-bound); 0.12 mmol)and stirred for 12 h. The polymer was filtered off with suction and thefiltrate was concentrated. The residue was purified by preparative HPLC.The product with the molecular weight of 524.11 (C30H38ClN3O3); MS(ESI): 524 (M+H+) was obtained in this way.

4-(4-Chloro-phenyl)-piperidine-1-carboxylic acid[4-((1S*,3R*,5R*)-8-aza-bicyclo[3.2.1]oct-3-yloxy)-phenyl]-amide

(1S*,3R*,5R*)-8-azabicyclo[3.2.1]octan-3-ol was protected by a standardprocess (di-tert-butyl dicarbonate, sodium hydroxide, THF/water) and theresulting carbonate was first reacted with 4-fluoronitrobenzene and thenhydrogenated by methods C and B. The resulting aniline((1S,3R,5R)-3-(4-Amino-phenoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester) was reacted by method A with4-(4-chlorophenyl)piperidine and finally the amine was liberated withtrifluoroacetic acid in dichloromethane. The product with the molecularweight of 439.99 (C25H30ClN3O2); MS (ESI): 440 (M+H+) was obtained inthis way.

The examples in table 3 were obtained by reacting4-(4-chloro-phenyl)-piperidine-1-carboxylic acid[4-((1S*,3R*,5R*)-8-aza-bicyclo[3.2.1]oct-3-yloxy)-phenyl]-amide withthe appropriate carbonyl compounds by method F.

TABLE 3 Ex. Molecular Molecular ESI-MS No. Structure formula weight [M +H]⁺ 79

C31H40ClN3O3 538.14 538 80

C32H42ClN3O2 536.16 536 81

C30H40ClN3O2 510.13 510 82

C28H36ClN3O2 482.07 482 83

C29H34ClN5O2 520.08 520 84

C31H41ClN4O3 553.15 553 85

C31H42ClN3O3 540.15 540 86

C31H35ClN4O2 531.10 531 87

C29H38ClN3O3 512.10 512 88

C30H38ClN3O3 524.11 524Synthesis of Starting Materials which Cannot be Purchased

4-(Cyclopentanecarbonylamino)benzoic acid

4-Aminobenzoic acid ethyl ester was reacted by method E withcyclopentanecarboxylic acid, and the resulting ester was hydrolyzed byboiling with sodium hydroxide in aqueous ethanol. The product with themolecular weight of 233.27 (C13H15NO3); MS (ESI): 234 (M+H+) wasobtained in this way.

4-[(Cyclopent-1-enecarbonyl)amino]benzoic acid can be obtainedanalogously.

4-Cyclobutoxymethylbenzoic acid

Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solutionof cyclobutanol (0.7 g) in DMF (8 ml). After gas evolution ceased,4-bromomethylbenzoic acid methyl ester (1.0 g) was added. After 4 hours,the mixture was partitioned between water and ethyl acetate. The organicphase was dried over magnesium sulfate and concentrated. The esterobtained as crude product was hydrolyzed by boiling with sodiumhydroxide in aqueous ethanol. The product with the molecular weight of206.24 (C12H14O3); MS (ESI): 207 (M+H+) was obtained in this way.

4-Cyclobutoxymethyl-3-fluorobenzoic acid

Sodium hydride (50% in oil; 1.63 g) was cautiously added to a solutionof cyclobutanol (2.7 g) in DMF (12 ml). After gas evolution ceased,4-bromo-1-bromomethyl-2-fluorobenzene (10 g) was added at 0° C. After 6hours at room temperature, the mixture was cautiously hydrolyzed andthen partitioned between water and ethyl acetate. The organic phase wasdried over magnesium sulfate and concentrated.4-Bromo-1-cyclobutoxymethyl-2-fluorobenzene was obtained as crudeproduct in this way.

n-Butyllithium (1.6 M in hexane; 7.0 ml) was added to a solution of4-bromo-1-cyclobutoxymethyl-2-fluorobenzene (2.6 g) in THF (50 ml) at−78° C. After 15 minutes, dry ice (4.4 g) was added. After warming toroom temperature, the mixture was diluted with water and extracted withethyl acetate. The aqueous phase was acidified and again extracted withethyl acetate. The organic phase was dried over magnesium sulfate,filtered and concentrated. The product with the molecular weight of224.23 (C12H13FO3); MS (ESI): 225 (M+H+) was obtained in this way.

4-(Pyridin-2-yloxymethyl)benzoic acid

A mixture of 2-fluoropyridine (1.6 g), 4-bromobenzyl alcohol (3.08 g),potassium tert-butoxide (2.03 g) and N-methylpyrrolidone (12.8 ml) washeated at 100° C. by microwave irradiation for one minute. The mixturewas diluted with water and extracted with ethyl acetate. The organicphase was dried over magnesium sulfate, filtered and concentrated.2-(4-Bromobenzyloxy)pyridine was obtained in this way.

n-Butyllithium (1.6 M in hexane; 11.4 ml) was added to a solution of2-(4-bromobenzyloxy)pyridine (4.2 g) in THF (120 ml) at −78° C. After 15minutes, dry ice (7 g) was added. After warming to room temperature, themixture was diluted with water and extracted with ethyl acetate. Theaqueous phase was acidified and again extracted with ethyl acetate. Theorganic phase was dried over magnesium sulfate, filtered andconcentrated. The product with the molecular weight of 229.24(C13H11NO3); MS (ESI): 230 (M+H+) was obtained in this way.

5-Butoxypyridine-2-carboxylic acid

Sodium hydride (50% in oil, 250 mg) was added to5-hydroxypyridine-2-carboxylic acid benzhydryl ester (2.0 g) dissolvedin DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g)was added. The mixture was heated at 90° C. for 6 hours. It was dilutedwith water and extracted with ethyl acetate. The organic phase was driedover magnesium sulfate and concentrated. The residue was hydrogenated inanalogy to method B. The product with the molecular weight of 195.22(C10H13NO3); MS (ESI): 196 (M+H+) was obtained in this way.

5-Chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl

Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C.and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone(2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes,water was cautiously added, and the mixture was extracted with ethylacetate. The organic phase was dried over sodium sulfate, filtered andconcentrated. The residue was treated with thionyl chloride (3 g) for 24hours, and the concentrated reaction solution was purified bypreparative HPLC. The product with the molecular weight of 194.67(C10H11ClN2); MS (ESI): 195 (M+H+) was obtained in this way.

4-Cyclopentyloxyaniline

A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g),potassium carbonate (63.3 g) and DMF (300 ml) was heated at 80° C. for24 hours. Cooling was followed by dilution with water and extractionwith ethyl acetate. The organic phase was washed with water, dried overmagnesium sulfate and concentrated. The residue was hydrogenated bymethod B. The product with the molecular weight of 177.25 (C11H15NO); MS(ESI): 178 (M+H+) was obtained in this way.

Starting from the appropriate cyclic amino alcohols, reaction with4-fluoronitrobenzene by method C and subsequent hydrogenation resultedin the following anilines:

-   4-((S)-2-Benzyl-2-aza-bicyclo[2.2.2]oct-6-yloxy)-phenylamine;-   4-((7R,8aS)-2-Methyl-octahydro-pyrrolo[1,2-a]pyrazin-7-yloxy)-phenylamine;-   4-[(4R*,5S*)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-phenylamine;-   4-[(1R*,7aS*)-(Hexahydro-pyrrolizin-1-yl)oxy]-phenylamine;-   4-(Octahydro-quinolizin-1-yloxy)-phenylamine and-   4-((3aS*,4S*,6aR*)-2-Methyl-octahydro-cyclopenta[c]pyrrol-4-yloxy)-phenylamine.

The required cyclic amino alcohols were obtained by literature methods:

-   (7R,8aS)-2-Methyl-octahydro-pyrrolo[1,2-a]pyrazin-7-ol (J.    Heterocyclic Chem. 1999, 27, 2181);-   (4R*,5S*)-1-Aza-bicyclo[3.3.1]nonan-4-ol (lithium aluminum hydride    reduction of 1-aza-bicyclo[3.3.1]nonan-4-one (J. Med. Chem. 2003,    46, 2216));-   (1R*,7aS*)-Hexahydro-pyrrolizin-1-ol (Tetrahedron Lett. 1996, 52,    3757); Octahydro-quinolizin-1-ol (J. Org. Chem. 1964, 29, 2248) and-   (3aS*,4S*,6aR*)-2-Methyl-octahydro-cyclopenta[c]pyrrol-4-ol-   ((3aS*,4S*,6aR*)-2-Trityl-octahydro-cyclopenta[c]pyrrol-4-ol    (Eur. J. Med. Chem. 1991, 26, 889) was heated in a mixture of formic    acid and aqueous formaldehyde).

1. A compound of formula (I):

wherein: A, B, D, and G are, independently of one another, N or C(R3);wherein R3 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R4)(R5), SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl, CON(R6)(R7), N(R8)CO(R9), N(R10)SO₂(R11), CO(R12), or(CR13R14)_(x)-O(R15); wherein R4, R5, R6, R7, R8, R10 are, independentlyof one another, H or (C₁-C₈)-alkyl; or, alternatively, R4 and R5, R6 andR7, independently of one another, taken together with the nitrogen atomto which they are attached form a 5-6 membered ring which optionally maycontain an additional heteroatom selected from the group consisting ofNH, N—(C₁-C₆)-alkyl, oxygen and sulfur; R9, R11, and R12 are,independently of one another, H, (C₁-C₈)-alkyl or aryl; R13 and R14 are,independently of one another, H or (C₁-C₈)-alkyl; R15 is H,(C₁-C₆)-alkyl or aryl; x is 0, 1, 2, 3, 4, 5 or 6; R1 is H,(C₁-C₈)-alkyl, (C₃-C₆)-alkenyl, or (C₃-C₆)-alkynyl; X is N(R16), O, abond, (R17)C═C(R18), C≡C, or a group of the formula (CR19R20)_(y), inwhich one or two (CR19R20) groups may be replaced by Y; Y is O, S,N(R21), or C═O; R16, R17, and R18 are, independently of one another, Hor (C₁-C₈)-alkyl; R19 and R20 are, independently of one another, H or(C₁-C₄)-alkyl; y is 1, 2, 3, 4, 5 or 6; R21 is H or (C₁-C₈)-alkyl; E isa 3-14 membered bivalent carbo- or heterocyclic ring structure having0-4 heteroatoms selected from the group consisting of N, O and S, whichring structure may optionally have substituents selected from the groupconsisting of H, F, Cl, Br, I, OH, CF₃, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,(C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R22)(R23),SO₂—CH₃, CON(R24)(R25), N(R26)CO(R27), N(R28)SO₂(R29), and CO(R30) andmay be mono- or bicyclic, wherein E is not a tetrazol-5-yl group; R22,R23, R24, R25, R26, and R28 are, independently of one another, H,(C₁-C₈)-alkyl or aryl; or, alternatively, R22 and R23, R24 and R25,independently of one another, taken together with the nitrogen atom towhich they are attached form a 5-6 membered ring which optionally maycontain an additional heteroatom selected from the group consisting ofNH, N—(C₁-C₆)-alkyl, oxygen and sulfur; R27, R29 and R30 are,independently of one another, H, (C₁-C₈)-alkyl or aryl; K is a bond,C≡C, (R31)C═C(R32), or a group of the formula (CR33R34)_(z) in which oneor more (CR33R34) groups may be replaced by Z; R31 and R32 are,independently of one another, H or (C₁-C₈)-alkyl; Z is O, S, N(R40), CO,SO, or SO₂; R33 and R34 are, independently of one another, H,(C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, hydroxy, or(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; z is 1, 2, 3, 4, 5 or 6; R40 is H or(C₁-C₈)-alkyl; R2 is H, (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy-(C₁-C₄)-alkyl,(C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, or a 3 to 10-membered mono-, bi-, tri-or spirocyclic ring which may include 0 to 4 heteroatoms selected fromthe group consisting of oxygen, nitrogen and sulfur, wherein the ringsystem may additionally be substituted with one or more of the followingsubstituents: F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R41),CON(R42)(R43), hydroxy, COO(R44), N(R45)CO(C₁-C₆)-alkyl, N(R46)(R47),SO₂CH₃, SCF₃ and S—(C₁-C₆)-alkyl, and wherein R2 is not a tetrazol-5-ylgroup; R41, R42, R43, R44, R45, R46, and R47 are, independently of oneanother, H or (C₁-C₈)-alkyl; or, alternatively, R42 and R43, R46 andR47, independently of one another, taken together with the nitrogen atomto which they are attached form a 5-6 membered ring which optionally maycontain an additional heteroatom selected from the group consisting ofNH, N—(C₁-C₆)-alkyl, oxygen and sulfur; E, K and R2 together form atricyclic system wherein the rings may be, independently of one another,saturated, partially saturated or unsaturated and, in each case,comprise 3- 8 ring atoms; L is O; Q is:

R91 is H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, CO(R92), (CR93R94)_(O′)-R95, or CO(CR93R94)_(p′)-R96;R92 is H or (C₁-C₈)-alkyl; R93 and R94 are, independently of oneanother, H, (C₁-C₈)-alkyl, OH, (C₃-C₈)-cycloalkyl, or(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; o′ and p′ are, independently of oneanother, 0, 1, 2, 3, 4, 5 or 6; R95 and R96 are, independently of oneanother, OH, O—(C₁-C₈)-alkyl, CON(R97)(R98), N(R99)CO(R100),N(R101)(R102), CO₂(R103), SO₂Me, CN, or a 3-10 membered ring systemhaving 0 to 3 heteroatoms selected from the group consisting of N, O andS, and which may be substituted with one or more of the followingsubstituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO(R104),oxo, and OH; R97, R98, R99, R100, R103, and R104 are, independently ofone another, H or (C₁-C₈)-alkyl; or, alternatively, R97 and R98 takentogether with the nitrogen atom to which they are attached form a 5-6membered ring which optionally may contain an additional heteroatomselected from the group consisting of NH, N—(C₁-C₆)-alkyl, oxygen andsulfur; R101 and R102 are, independently of one another, H,(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, CO(R105), (CR106R107)_(q ′)-R108, orCO(CR109R110)_(r′)-R111; or, alternatively, R101 and R102 form, togetherwith the nitrogen atom to which they are bonded, a 4 to 10-memberedmono-, bi- or spirocyclic ring which, apart from the nitrogen atom,comprises 0 to 3 additional heteroatoms selected from the groupconsisting of N, O and S and which ring may additionally be substitutedwith one or more of the following substituents: F, Cl, Br, CF₃,O—(C₁-C₈)-alkyl, (C₁-C₆)-alkyl, CO(R112), oxo, OH,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114),N(R115)CO(R116), N(R117)(R118), CO₂(R119), and SO₂Me; R105, R106, R107,R109, R110, R112, R113, R114, R115, R116, R117, R118, and R119 are,independently of one another, H or (C₁-C₈)-alkyl; or, alternatively,R117 and R118 taken together with the nitrogen atom to which they areattached form a 5-6 membered ring which optionally may contain anadditional heteroatom selected from the group consisting of NH,N—(C₁-C₆)-alkyl, oxygen and sulfur; q′ and r′ are, independently of oneanother, 0, 1, 2, 3, 4, 5 or 6; R108 is selected from the groupconsisting of H, (C₁-C₈)-alkyl, OH, O—(C₁-C₈)-alkyl, CON(R120)(R121),N(R122)CO(R123), N(R124)(R125), CO₂ R126 SO₂Me, CN, and a 3-10 memberedring system having 0 to 3 heteroatoms selected from the group consistingof N, O and S, which ring system may be substituted with one or more ofthe following substituents: F, Cl, Br, CF₃(C₁-C₈)-alkyl,O—(C₁-C₈)-alkyl, CO(R127), oxo, and OH; R111 is selected from the groupconsisting of OH, O—(C₁-C₈)-alkyl, CON(R120)(R121), N(R122)CO(R123),N(R124)(R125), CO₂(R126), SO₂Me, CN, and a 3-10 membered ring systemhaving 0 to 3 heteroatoms selected from the group consisting of N, O andS, which ring system may be substituted with one or more of thefollowing substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl, CO(R127), oxo,and OH; R120, R121, R122, R123, R124, R125, R126, and R127 are,independently of one another, H or (C₁-C₈)-alkyl; or, alternatively,R120 and R121, R124 and R125, independently of one another, takentogether with the nitrogen atom to which they are attached form a 5-6membered ring which optionally may contain an additional heteroatomselected from the group consisting of NH, N—(C₁-C₆)-alkyl, oxygen andsulfur; or an N-oxide thereof or a physiologically tolerated saltthereof.
 2. The compound according to claim 1, wherein: A, B, D, and Gare, independently of one another, N or C(R3); R3 is H, F, Cl, Br, CF₃,CN, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl,N(R4)(R5), SO₂-CH₃, CON(R6)(R7), N(R8)CO(R9), CO(R12), or(CR13R14)_(x)-O(R15); R4, R5, R6, R7, and R8 are, independently of oneanother, H or (C₁-C₆)-alkyl; or, alternatively, R4 and R5, R6 and R7,independently of one another, taken together with the nitrogen atom towhich they are attached form a 5 membered ring; R9 and R12 are,independently of one another, H or (C₁-C₄)-alkyl; R13 and R14 are eachH; R15 is H or (C₁-C₆)-alkyl; x is 0, 1 or 2; R1 is H or (C₁-C₈)-alkyl;X is N(R16), a bond, (R17)C═C(R18), C≡C, CH₂—CH₂, YCH₂, or CH₂Y; Y is O,S or N(R21); R16, R17 and R18 are, independently of one another, H or(C₁-C₈)-alkyl; R21 is H or (C₁-C₈)-alkyl; E is a 3-8 membered bivalentcarbo- or heterocyclic ring structure having 0-4 heteroatoms selectedfrom the group consisting of N, O and S, which ring may optionally havesubstituents selected from the group consisting of H, F, Cl, Br, OH,CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—(C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R22)(R23), SO₂—CH₃, N(R26)CO(R27),N(R28)SO₂(R29), and CO(R30) and may be mono- or bicyclic, provided thatE is not a tetrazol-5-yl group; R22 and R23 are, independently of oneanother, H or (C₁-C₈)-alkyl; or, alternatively, R22 and R23 takentogether with the nitrogen atom to which they are attached form a 5membered ring; R27, R29 and R30 are, independently of one another, H or(C₁-C₈)-alkyl; K is a bond, O , OCH₂, CH₂O, S, SO, SO₂, N(R40),N(R40)CO, N—SO₂, CON(R40), (C(R33)(R34))_(z), CO, (R31)C═C(R32), C≡C,SCH₂, SO₂CH₂; z is 1, 2 or 3; R31, R32, R33, R34, and R40 are,independently of one another, H or (C₁-C₈)-alkyl; R2 is (C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or a 3 to 10-membered mono-, bi-, tri- orspirocyclic ring which may include 0 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, wherein the ring systemmay additionally be substituted with one or more of the followingsubstituents: F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,(C₀-C₂)-alkylene-aryl, oxo, CO(R41), CON(R42)(R43), hydroxy,N(R45)CO(C₁-C₆)-alkyl, N(R46)(R47) or SO₂CH₃; preferably (C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or bicyclic ringwhich may include 0 to 2 heteroatoms selected from the group consistingof oxygen, nitrogen and sulfur, where the ring system may additionallybe substituted with F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,oxo, CO(R41), CON(R42)(R43), N(R45)CO(C₁-C₆)-alkyl and SO₂CH₃; R41, R42,R43, R45, R46 and R47 are, independently of one another, H or(C₁-C₈)-alkyl; or R42 and R43, R46 and R47, independently of oneanother, taken together with the nitrogen atom to which they areattached form a 5 membered ring; L is O ; Q is:

R91 is H, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, CO(R92), (CR93R94)_(o′)-R95, or CO(CR93R94)_(p′)-R96;R92 is H or (C₁-C₈)-alkyl; R93 and R94 are, independently of oneanother, H, (C₁-C₈)-alkyl, OH, (C₃-C₈)-cycloalkyl, or(C₁-C₄)-alkoxy-(C₁-C₄)alkyl; o′ and p′ are, independently of oneanother, 0, 1, 2, 3, 4, 5 or 6, R95 and R96 are, independently of oneanother, OH, O—(C₁-C₈)-alkyl, CON(R97)(R98), N(R99)CO(R100),N(R101)(R102), CO₂(R103), SO₂Me, CN, or a 3-10 membered ring systemhaving 0 to 3 heteroatoms selected from the group consisting of N, O andS, which ring system may be substituted with one or more of thefollowing substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl,CO(R104), oxo, and OH; R97, R98, R99, R100, R103 and R104 are,independently of one another, H or (C₁-C₈)-alkyl; or, alternatively, R97and R98 taken together with the nitrogen atom to which they are attachedform a 5-6 membered ring which optionally may contain an additionalheteroatom selected from the group consisting of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur; R101 and R102 are, independently of one another, H,(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, CO(R105), (CR106R107)_(q′)-R108, orCO(CR109R110)_(r′)-R111; or, alternatively, R101 and R102 form, togetherwith the nitrogen atom to which they are bonded, a 4 to 10-memberedmono-, bi- or spirocyclic ring which, apart from the nitrogen atom,comprises 0 to 3 additional heteroatoms selected from the groupconsisting of N, O and S and may additionally be substituted with one ormore of the following substituents: F, Cl, Br, CF₃, O—(C₁-C₈)-alkyl,(C₁-C₆)-alkyl, CO(R112), oxo, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl, CON(R113)(R114), N(R115)CO(R116), N(R117)(R118),CO₂(R119), and SO₂Me; R105, R106, R107, R109, R110, R112, R113, R114,R115, R116, R117, R118 and R119 are, independently of one another, H or(C₁-C₈)-alkyl; or, alternatively, R117 and R118 taken together with thenitrogen atom to which they are attached form a 5-6 membered ring whichoptionally may contain an additional heteroatom selected from the groupconsisting of NH, N-(C₁-C₆)-alkyl, oxygen and sulfur; q′ and r′ are,independently of one another, 0, 1, 2, 3, 4, 5 or 6; R108 is selectedfrom the group consisting of H (C₁-C₈)-alkyl, OH, O—(C₁-C₈)-alkyl,CON(R120)(R121), N(R122)CO(R123), N(R124)(R125), CO₂(R126),SO₂Me, CN,and a 3-10membered ring system having 0 to 3 heteroatoms selected fromthe group consisting of N, O and S, which ring system may be substitutedwith one or more of the following substituents: F, Cl, Br, CF₃(C₁-C₈)-alkyl, O—(C₁-C₈)-alkyl, CO (R127), oxo, and OH; R111 is selectedfrom the group consisting of OH, O—(C₁-C₈)-alkyl, CON(R120)(R121),N(R122)CO(R123), N(R124)(R125), CO₂(R126), SO₂Me, CN, or a 3-10 memberedring system having 0 to 3 heteroatoms selected from the group consistingof N, O and S, which ring system may be substituted with one or more ofthe following substituents: F, Cl, Br, CF₃, (C₁-C₈)-alkyl,O—(C₁-C₈)-alkyl, CO(R127), oxo, and OH; R120, R121, R122, R123, R124,R125, R126 and R127 are, independently of one another, H or(C₁-C₈)-alkyl; or, alternatively, R120 and R121, R124 and R125,independently of one another, taken together with the nitrogen atom towhich they are attached form a 5-6 membered ring which optionally maycontain an additional heteroatom selected from the group consisting ofNH, N—(C₁-C₆)-alkyl, oxygen and sulfur; or an N-oxide thereof or aphysiologically tolerated salt thereof.
 3. The compound according toclaim 1, wherein the total number of nitrogen atoms in the ring holdingA, B, D, and G is 0-2.
 4. The compound according to claim 1, wherein: Kis selected from O , OCH₂, CH₂O, S, SO, SO₂, N(R40), N(R40)CO, CON(R40),(C(R33)(R34))_(z), CO, (R31)C═C(R32), C≡C, SCH₂, and SO₂CH₂; wherein zis 1, 2 or 3; and R31, R32, R33, R34, and R40 are, independently of oneanother, H or (C₁-C₈)-alkyl.
 5. The compound according to claim 1,wherein: A, B, D, and G are, independently of each other, C(R3); whereinR3 is H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R4)(R5), SO₂—CH₃,CON(R6)(R7), N(R8)CO(R9), CO(R12), or (CR13R14)_(x)-O(R15); R4, R5, R6,R7, and R8 are, independently of one another, H or (C₁-C₈)-alkyl; or,alternatively, R4 and R5, R6 and R7 form, independently of one another,together with the nitrogen atom to which they are bonded, a 5-6 memberedring which optionally may contain an additional heteroatom selected fromthe group consisting of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; R9 andR12 are, independently of one another, H or (C₁-C₈)-alkyl; R13 and R14are each H; R15 is H or (C₁-C₆)-alkyl; and x is 0, 1 or
 2. 6. Thecompound according to claim 1, wherein X is a bond or N(R16), in whichR16 is H or (C₁-C₈)-alkyl.
 7. A pharmaceutical composition comprisingone or more compounds according to claim 1 or a physiologicallyacceptable salt thereof in combination with at least onepharmaceutically acceptable excipient.
 8. A pharmaceutical compositioncomprising one or more compounds according to claim 2 or aphysiologically acceptable salt thereof in combination with at least onepharmaceutically acceptable excipient.
 9. A method for the treatment ofobesity which comprises administering to a patient in need of saidtreatment an effective amount of a compound of claim 1 or aphysiologically acceptable salt thereof.
 10. A method for the treatmentof obesity which comprises administering to a patient in need of saidtreatment an effective amount of a compound of claim 2 or aphysiologically acceptable salt thereof.